The control and cure of cancer represents one of our most challenging health problems. The treatment of cancer can be approached by several modes of therapy including surgery, radiation, chemotherapy or a combination of any of these treatments. Chemotherapy continues to be an indispensable therapy for inoperable or metastatic forms of the disease.
The selection of natural compounds, or the synthesis of new compounds having effective anticancer activity is complicated by the still limited knowledge of cancer cell biology and biochemistry. Therefore, development of new effective anti-tumor agents will remain heavily dependent on screening compounds to discover novel compounds having cytotoxic activity. Preferably, such compounds exhibit enhanced cytotoxicity against tumor cells relative to their cytotoxicity to normal cells.
The success of novel antitumor drug development programs is dependent on the initial identification of antitumor agents. Thus the discovery of antitumor agents requires the systematic screening of a large number of natural products and synthetic compounds.
The mouse L1210 leukemia cell line was initially the preferred model system used for screening natural compounds for antitumor activity. However, the P388 murine leukemia system was found to be more sensitive and predictive than L1210 leukemia system, and has been used as primary screen during the past decade. Systematic screening for compounds exhibiting toxicity to these two leukemia cell lines has resulted in the isolation of a large number of active natural products. However, the anticancer activities of these compounds were predominantly in leukemia, lymphoma and a few rare tumors. Low clinical efficacy, or the lack of clinical efficacy of known chemotherapeutics against slower growing solid tumors, is a serious concern.
It has been recognized that the use of a single antileukemia screening system could bias the end results and lead to the isolation of compounds only active in the treatment of fast growing tumors. In addition, the use of a single antileukemia screening system may not detect novel compounds with high specificities for particular cell lines. It is also likely that many novel compounds with possible anti-tumor activity have remained undetected by the less sensitive in vivo models due to the low concentrations at which many active natural products occur.
Considering the diversity of tumors in terms of cell type, morphology, growth rate and other cellular characteristics, the U.S. National Cancer Institute (NCI) has developed a “disease-oriented” approach to antitumor activity screening (M. R. Boyd, in “Principle of Practice of Oncology” J. T. Devita, S. Hellman, S. A. Rosenberg (Eds.) Vol. 3, PPO Update, No. 10, 1989). This in vitro prescreening system is based on the measurement of antitumor cytotoxicity against human tumor cell line panels consisting of approximately 60 cell lines of major human tumors (including leukemia and slower growing tumor cells such as lung, colon, breast, skin, kidney, etc.). The most important advantage of the new in vitro screening panels is the opportunity to identify compounds that are selectively more cytotoxic to cells of slowly growing solid tumors than to rapidly growing leukemia cells.
The cytotoxicity profile of the NCI human tumor cell panels displays the tumor specificity of a given compound, however the assay does not assess the toxicity of that compound to normal human cells. Accordingly a second bioassay is utilized to measure the selective cytotoxicity against certain types of tumor cells verses normal human cells.
The growth and differentiation of cells are regulated by signaling cascades induced by various mitogenic proteins (J. Kurjan and B. L. Taylor, “Signal Transduction,” Academic Press, New York, N.Y. 1994) that often are encoded by proto-oncogenes. The overexpression, amplification or mutation of the oncoprotein is critically involved in the initiation, progression and metastasis of malignant cells (R. A. Weinberg, “Oncogenes and the Molecular Origins of Cancer,” Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989). Many oncoproteins alter normal cellular growth regulation by modulating the intracellular signaling pathways from the membrane to the nucleus. Therefore, cancer may be considered as a disease of cellular signal transduction, which presents a novel approach for anticancer therapy. One of the critical enzymes involved in the oncoprotein signal transduction is protein kinase C (U. Nishizuka, Nature, 308, 693, 1984 and Science, 233, 305, 1986). Thus, the determination of a compound's ability to inhibit protein kinase C activity has become a good prognostic for discovering novel anticancer agents (A. Basu, Pharmac Ther, 59, 257, 1993). Furthermore it is anticipated that the selenophene compounds will demonstrate selectivity for certain class members of protein kinases, including protein kinase C. Inhibition of a specific classes of protein kinases will allow the treatment of other diseases associated with defects in signaling transduction.
Selenophenes are selenium containing heterocyclic compounds that are analogs of naturally occurring thiophene, furan and pyrrole compounds. Selenophenes have been found to be effective antitumor agents, and exhibit enhanced cytotoxicity against slow growing tumor cells, selective cytotoxicity against human renal, ovarian tumor cells, and skin tumor cells; and exhibit inhibition of protein kinase C.
In accordance with this invention there is provided a method for the treatment of cancer which utilizes selenophene compounds of the formula I: 
wherein R1 and R2 are independently selected from the group consisting of, H, CHO, CH2OH and CH2NH2;
X and Y are independently selected from the group consisting of Se, S, O, NCH3 and NH;
R3, R4, R5 and R6 are independently selected from the group consisting of H, CHO, CH2OH and CH2NH2; cyclodextrin complexes of such compounds; and when R3, R4, R5 or R6 is CH2NH2, the pharmaceutically acceptable salt of the compound represented thereby.
Further in accordance with this invention there are provided novel cytotoxic compounds of the above formula and chemotherapeutic pharmaceutical compositions containing said compounds in anti-tumor effective amounts.
Additional objects, features, and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description of preferred embodiments exemplifying the best mode of the invention as presently perceived.